1. Field of the Invention
The invention relates to new 2-substituted alkyl-3-carboxy carbapenems having the formula: ##STR3## with R.sup.1, R.sup.2, R.sup.3, X and Y defined hereafter as antibiotics and beta lactamase inhibitors produced by a novel Michael addition-elimination reaction of a substituted allyl azetidinone in the reaction shown: ##STR4## with R.sup.1, R.sup.2, Q, X and Y defined hereafter
2. Description of the Prior Art
2-Substituted alkyl-3-carboxy carbapenems are known to be effective antibiotics. For example, T. N. Salzmann et. al. in "Recent Advances in the Chemistry of .beta.-Lactam Antibiotics" P. H. Bentley and R. Southgate eds., Royal Society of Chemistry, 1989, pp 171-189 discloses carbapenems of this type as having antibacterial activity.
Sandoz reported in Tetrahedron Letters, Vol. 25, No. 52, pp. 5989-5992 (1984) the intermolecular Wittig reaction between 2-oxocarbapenem-3-carboxylic esters and triphenylphosphorane ylides as shown gives exo and endo ##STR5## mixtures of product (dotted lines represent mixtures of endocyclic and exocyclic double bonds) wherein W=CN, CO.sub.2 CH.sub.3 and COCH.sub.3 and R.sup.7 =H, R.sup.5 =ethyl or fluoroethyl and R.sup.6 is either an ester group or a cationic species.
In EP 0265 117, published April 4, 1988, the same method of 2-alkyl-3-carboxy carbapenem synthesis using Wittig methodology is disclosed. In this disclosure V=CN, COR.sup.8 or CO.sub.2 R.sup.8 ; R.sup.8 is C.sub.1 -C.sub.4 alkyl, C.sub.7 -C.sub.11 araalkyl; R.sup.9 =H, C.sub.1 -C.sub.4 alkyl; R.sup.10 =hydroxyethyl or protected hydroxyethyl; R.sup.11 =ester protecting group. ##STR6##
Stated in both publications was that the intermolecular Wittig reaction method gave much higher yields over the conventionally used intramolecular approach shown below (where W, R.sup.10 and R.sup.11 have the same distinction as before) and therefore was the method of choice. ##STR7## The selection of R.sup.7 and R.sup.9 in these disclosures is limited to H or C-substitution. Other substituents at this position such as halogens, i.e., chlorine would not be tolerated in either reaction mode (inter or intramolecular Wittig reaction). Indeed, a comprehensive literature search reveals no report of a triarylphosphorane species with general structure shown where W.sup.1 has the same designation as W and V before and Z=halogen (F, Cl, Br, I). ##STR8## Thus, it is highly unlikely that 2-haloalkyl-3-carboxyl carbapenems could be prepared by Wittig methodology. However, such compounds can be prepared by the intramolecular Michael addition-elimination method of this invention.
In Japanese Patent Application No. 58-103,388 (Sankyo) published Jun. 20, 1983, carbapenems of the formula shown below are prepared via an intramolecular Wittig reaction where B, A and R.sup.12 ##STR9## have the following designation: B is thio, sulfinyl, or sulfonyl; A is either a single bond or a linear or branched-chain alkylene; R.sup.12 is a cyclic amine residue that forms a 3- to 8-membered ring overall and may include within the ring an oxygen, nitrogen, sulfur, sulfinyl, sulfonyl, or carbonyl, which nitrogen may be substituted with a lower aliphatic acyl that may have an amino group, lower alkyl-monosubstituted amino- or lower alkyl-disubstituted aminoalkylene, or a group of the formula ##STR10## (wherein R.sup.13 is hydrogen, amino, or a lower alkyl; and R.sup.14 is hydrogen or a lower alkyl), in addition to which a group of the formula ##STR11## (wherein R.sup.15 is hydrogen or lower alkyl) present on the acyl or alkyl substituent on said cyclic amine residue may be replaced with a group having the formula ##STR12## (wherein R.sup.13, R.sup.14 and R.sup.15 have the same meaning as above).
The Sankyo disclosure provides no teaching or suggestion on the preparation of novel exocyclic double bond isomers shown below. ##STR13##
By the Sankyo method of ring closure (intramolecular Wittig reaction) neither the E nor Z exoproduct isomers are possible, only endocyclic double bond isomers. These two exo isomeric products can be produced by the method involving the Michael-addition-elimination sequence disclosed in this invention. Additionally, the Sankyo disclosure provided no in vitro antibacterial activity data.
In Heterocycles, Vol. 23, No. 8, pp. 1915-1919 (1985) the Sandoz group reported a 2-alkyl-3-carboxy carbopenem shown via an intramolecular Wittig reaction ##STR14## No antibacterial data of this carbapenem is provided in the disclosure.
It is an object of this invention to provide novel families of carbapenem antibiotics via a new and general chemical process that utilizes a Michael addition-elimination reaction of substituted allyl azetidinone intermediates. These intermediates also comprise a new and useful form of carbapenem precursor.